Nepicastat for Posttraumatic Stress Disorder (PTSD) in OIF/OEF Veterans

• Sponsor: Tuscaloosa Research & Education Advancement Corporation (Other)
• Overall Status: Completed
• CT.gov ID: NCT00659230
• Collaborator: Acorda Therapeutics (Industry), Ralph H. Johnson VA Medical Center (U.S. Fed), Baylor College of Medicine (Other), San Diego Veterans Healthcare System (U.S. Fed), James J. Peters Veterans Affairs Medical Center (U.S. Fed)
• Enrollment: 100
• Locations: 3
• Arms: 2
• Actual Duration (Months): 38
• Patients Per Site: 33.3
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This study proposes a multi-site, randomized, double-blind, placebo-controlled clinical trial of the dopamine-ß-hydroxylase (DBH) inhibitor, nepicastat, for the treatment of posttraumatic stress disorder (PTSD) in outpatients who have previously served in a combat zone during Operation Iraqi Freedom and Operation Enduring Freedom (OIF/OEF)or other Southwest conditions since 19800. A DBH inhibitor's mechanism of action is to decrease neuronal noradrenaline (NA) release by inhibiting DBH conversion of dopamine (DA) to NA. Animal models of PTSD and human studies have found a substantial increase in NA activity for these animal models and for PTSD in humans. Furthermore, recent clinical studies have improved PTSD hyper-arousal symptoms by reducing the NA over-activity using agents like NA post-synaptic antagonists. Key support for the proposed study is based on a similar improvement in PTSD symptoms after treatment with the DBH inhibitor, disulfiram.

In the experience of the clinical investigators, the most common chief complaint of the OIF/OEF veterans with PTSD is hyperarousal (DSM-IV criterion D symptom cluster). These symptoms significantly interfere with social, occupational, and interpersonal function. Standard treatments with antidepressants are not fully effective in treating the symptoms of PTSD in veterans; thus, new treatments are needed. An intervention, such as nepicastat, aimed at reducing hyperarousal, as well as other PTSD symptoms, would have significant impact of restoring overall function and quality of life in OIF/OEF veterans with PTSD. Since hyperarousal symptoms responded relatively quickly to medications of this type, our study in 120 outpatient veterans with PTSD will compare nepicastat 120 mg/day vs. placebo in a 6-week double-blind, randomized clinical trial (RCT). The veterans will be followed for an additional 8 weeks after the RCT, during which, those who have a priori defined positive clinical response to the study medication, nepicastat vs. placebo, will be continued on the study medication, in order to assess further improvement and safety. Those patients who do not have a positive clinical response during the 6 week RCT will be offered the addition of the standard first-line PTSD pharmacotherapy, paroxetine, during the 8 weeks extension phase. Thus, weeks 7-14 offer an opportunity to evaluate longer-term nepicastat efficacy and to compare the treatment response of nonresponders after augmentation with paroxetine.

Condition or Disease	Intervention/Treatment	Phase
Posttraumatic Stress Disorder	Drug: Nepicastat; Drug: Placebo	Phase 2

Detailed Description

HYPOTHESES Primary Hypothesis: Compared to placebo treatment, nepicastat-treated OIF/OEF veterans with PTSD will have significantly reduced PTSD hyperarousal symptoms as defined by the Clinician Administered PTSD Scale [CAPS], subscale D (CAPS-D).

Secondary Hypotheses: Compared to placebo, nepicastat-treated OIF/OEF veterans with PTSD will have:

• Significantly reduced PTSD symptoms (total CAPS)

• Significantly reduced PTSD reexperiencing symptoms (CAPS-B)

• Significantly reduced PTSD avoidance symptoms (CAPS-C)

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo-Controlled Trial of the Dopamine-B-Hydroxylase (DBH) Inhibitor, Nepicastat, for the Treatment of PTSD in OIF/OEF Veterans
• Actual Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Jul 5, 2012
• Actual Study Completion Date: Aug 30, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Arm 1	Drug: Placebo; 100-800mg placebo
Active Comparator: Nepicastat Arm 2	Drug: Nepicastat; 100-800mg; Other Names: SYN117 Dopamine beta hydroxylase (DBH) inhibitor

Outcome Measures

Primary Outcome Measures

1. Clinician Administered PTSD Scale Subscore D (Hyperarousal) [Baseline, week 2, 4 and 6]

   The Clinician Administered PTSD Scale subscore D (CAPS-D) measures the hyperarousal cluster for PTSD symptoms (5 items). Higher scores indicate greater severity. Range for CAPS-D is zero to 40. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (κ=0.78).

Secondary Outcome Measures

1. Clinician Administered PTSD Scale Total Score [Baseline, week 2,4, and 6]

   The Clinician Administered PTSD Scale (CAPS) measures the full spectrum of PTSD symptoms. Higher scores indicate greater severity. Range for CAPS is zero to 136. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (κ=0.78).

2. Clinician Administered PTSD Scale Subscale B Score [6 weeks]

   The Clinician Administered PTSD Subscale B (CAPS-B) measures the re-experiencing cluster of PTSD symptoms. Higher scores indicate greater severity. Range for CAPS-B is zero to 40. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (κ=0.78). Blake, D.D., Weathers, F.W., Nagy, L.M., Kaloupek, D.G., Gusman, F.D., Charney, D.S., Kean, T.M., 1995, The development of a clinician-administered PTSD scale. Journal of Traumatic Stress, 8:75-90.

3. Clinician Administered PTSD Scale Subscale C Score [Baseline, week 2, 4, and 6]

   The Clinician Administered PTSD Subscale C (CAPS-C) measures the Avoidance and emotional numbing cluster of PTSD symptoms. Higher scores indicate greater severity. Range for CAPS-C is zero to 56. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (κ=0.78).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Signed informed consent

• Patient understands the risks and benefits and agrees to visit frequency and procedures

• Male or female

• Any race or ethnic origin

• Served in OIF/OEF or Afghanistan conflicts or other Southwest Asia conditions

• Currently Active Duty, National Guard, Reservist, Veteran, and/or Retired Military

• Diagnosis of PTSD (by MINI (Mini International Neuropsychiatric Interview) and CAPS-DX (Clinician Administered PTSD scale- Diagnostic Form) using Rule of Fours and total CAPS-DX score of 45)

• No substance use disorders in the previous 2 weeks and no substance dependence disorders in the past 4 weeks (except for nicotine and caffeine)

• Free of psychotropic medication for 2 weeks prior to randomization

• Physical and laboratory panel are within normal limits or not clinically significant

• Women of childbearing potential must be using medically-approved methods of birth control

• ≥19 to 65 years of age

Exclusion Criteria:

• Lifetime history of bipolar I, schizophrenia, schizoaffective or cognitive disorders

• Actively considering plans of suicide or homicide

• Psychotic symptoms that in the investigator's opinion impair the patient's ability to give informed consent or make it unsafe for patient to be maintained without a neuroleptic

• Unstable general medical conditions or a contraindication to the use of nepicastat

• Women planning to become pregnant or breastfeed during the study

• Current or pending incarceration

• Terminal Illness

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tuscaloosa VAMC	Tuscaloosa	Alabama	United States	35404
2	VA San Diego Healthcare System	San Diego	California	United States	92161
3	James J.Peters VA Medical Center	The Bronx	New York	United States	10468

Sponsors and Collaborators

• Tuscaloosa Research & Education Advancement Corporation
• Acorda Therapeutics
• Ralph H. Johnson VA Medical Center
• Baylor College of Medicine
• San Diego Veterans Healthcare System
• James J. Peters Veterans Affairs Medical Center

Investigators

• Study Chair: Carlos Berry, M.D., IRB Tuscaloosa VAMC

Study Documents (Full-Text)

None provided.

More Information

Publications

• Graham DP, Nielsen DA, Kosten TR, Davis LL, Hamner MB, Makotkine I, Yehuda R. Examining the utility of using genotype and functional biology in a clinical pharmacology trial: pilot testing dopamine β-hydroxylase, norepinephrine, and post-traumatic stress disorder. Psychiatr Genet. 2014 Aug;24(4):181-2. doi: 10.1097/YPG.0000000000000039.
• Kosten TR, Krystal J. Biological mechanisms in posttraumatic stress disorder. Relevance for substance abuse. Recent Dev Alcohol. 1988;6:49-68. Review.

• Responsible Party: Lori Davis, MD, Associate Chief of Staff, Tuscaloosa Research & Education Advancement Corporation
• ClinicalTrials.gov Identifier: NCT00659230
• Other Study ID Numbers: 08-06; PT074384/W81XWH-08-2-0071; PT074384/W81XWH-09-1-0287
• First Posted: Apr 16, 2008
• Last Update Posted: Oct 13, 2017
• Last Verified: Sep 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Lori Davis, MD, Associate Chief of Staff, Tuscaloosa Research & Education Advancement Corporation: PTSD; Veterans; Nepicastat; OIF/OEF
• Additional relevant MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Dopamine

Study Results

Participant Flow

Arm/Group Title	Placebo	Nepicastat
Arm/Group Description	Arm 1 Placebo: 100-800mg placebo	Arm 2 Nepicastat: 100-800mg
Period Title: Overall Study
STARTED	51	49
COMPLETED	42	37
NOT COMPLETED	9	12

Baseline Characteristics

Arm/Group Title	Placebo	Nepicastat	Total
Arm/Group Description	Arm 1 Placebo: 100-800mg placebo	Arm 2 Nepicastat: 100-800mg	Total of all reporting groups
Overall Participants	46	45	91
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.61 (10.49)	39.33 (11.01)	37.96 (10.88)
Sex: Female, Male (Count of Participants)
Female	4 8.7%	1 2.2%	5 5.5%
Male	42 91.3%	44 97.8%	86 94.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 4.3%	5 11.1%	7 7.7%
Not Hispanic or Latino	44 95.7%	40 88.9%	84 92.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	22 47.8%	22 48.9%	44 48.4%
White	21 45.7%	16 35.6%	37 40.7%
More than one race	3 6.5%	7 15.6%	10 11%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	46 100%	45 100%	91 100%
CAPS-D Score (primary outcome) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	25.59 (6.17)	26.07 (6.01)	25.82 (6.06)

Outcome Measures

1. Primary Outcome

Title	Clinician Administered PTSD Scale Subscore D (Hyperarousal)
Description	The Clinician Administered PTSD Scale subscore D (CAPS-D) measures the hyperarousal cluster for PTSD symptoms (5 items). Higher scores indicate greater severity. Range for CAPS-D is zero to 40. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (κ=0.78).
Time Frame	Baseline, week 2, 4 and 6

Outcome Measure Data

Analysis Population Description

Participants who returned for at least one post-randomization visit and had source documentation (in placebo group 2 did not return and the source documentation for 5 participants was lost; for nepicastat group 3 did not return and the source documentation for 4 participants was lost).

Arm/Group Title	Placebo	Nepicastat
Arm/Group Description	Arm 1 Placebo: 100-800mg placebo	Arm 2 Nepicastat: 100-800mg
Measure Participants	44	42
Baseline	25.59 (6.17)	26.07 (6.01)
Week 2	21.20 (7.59)	22.07 (7.95)
Week 4	19.78 (8.27)	21.15 (8.13)
Week 6	19.57 (8.55)	21.62 (9.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nepicastat
	Comments	The analysis was conducted using a repeated-measures analysis of variance (ANOVA) model. The model consisted of two factors - treatment at two levels and time (5 time points including baseline) and group by time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.723
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Effect Size
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 90%; -0.64 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Effect size (ES) for change in CAPS-D score relative to baseline was calculated according to the method of Cohen.

2. Secondary Outcome

Title	Clinician Administered PTSD Scale Total Score
Description	The Clinician Administered PTSD Scale (CAPS) measures the full spectrum of PTSD symptoms. Higher scores indicate greater severity. Range for CAPS is zero to 136. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (κ=0.78).
Time Frame	Baseline, week 2,4, and 6

Outcome Measure Data

Analysis Population Description

Participants who returned for at least one post-randomization visit and had source documentation (in placebo group 2 did not return and the source documentation for 5 participants was lost; for nepicastat group 3 did not return and the source documentation for 4 participants was lost).

Arm/Group Title	Placebo	Nepicastat
Arm/Group Description	Arm 1 Placebo: 100-800mg placebo	Arm 2 Nepicastat: 100-800mg
Measure Participants	44	42
Baseline	74.52 (16.73)	77.18 (16.55)
Week 2	61.82 (25.02)	60.17 (24.72)
Week 4	52.61 (27.17)	60.26 (27.59)
Week 6	58.22 (28.37)	52.95 (25.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nepicastat
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.540
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Effect Size
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 90%; -.52 to 0.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	Effect size (ES) for change in CAPS-D score relative to baseline was calculated according to the method of Cohen.

3. Secondary Outcome

Title	Clinician Administered PTSD Scale Subscale B Score
Description	The Clinician Administered PTSD Subscale B (CAPS-B) measures the re-experiencing cluster of PTSD symptoms. Higher scores indicate greater severity. Range for CAPS-B is zero to 40. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (κ=0.78). Blake, D.D., Weathers, F.W., Nagy, L.M., Kaloupek, D.G., Gusman, F.D., Charney, D.S., Kean, T.M., 1995, The development of a clinician-administered PTSD scale. Journal of Traumatic Stress, 8:75-90.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

Participants who returned for at least one post-randomization visit and had source documentation (in placebo group 2 did not return and the source documentation for 5 participants was lost; for nepicastat group 3 did not return and the source documentation for 4 participants was lost).

Arm/Group Title	Placebo	Nepicastat
Arm/Group Description	Arm 1 Placebo: 100-800mg placebo	Arm 2 Nepicastat: 100-800mg
Measure Participants	44	42
Baseline	20.37 (7.26)	20.41 (8.46)
Week 2	16.95 (9.77)	14.14 (8.97)
Week 4	11.51 (10.02)	14.59 (9.75)
Week 6	12.64 (10.04)	15.27 (10.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nepicastat
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.951
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Effect size
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 90%; -0.64 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Effect size (ES) for change in CAPS-D score relative to baseline was calculated according to the method of Cohen.

4. Secondary Outcome

Title	Clinician Administered PTSD Scale Subscale C Score
Description	The Clinician Administered PTSD Subscale C (CAPS-C) measures the Avoidance and emotional numbing cluster of PTSD symptoms. Higher scores indicate greater severity. Range for CAPS-C is zero to 56. The CAPS has acceptable test-retest reliability (0.98), sensitivity (0.84), specificity (0.95), internal consistency (0.76-0.88) and validity (κ=0.78).
Time Frame	Baseline, week 2, 4, and 6

Outcome Measure Data

Analysis Population Description

Participants who returned for at least one post-randomization visit and had source documentation (in placebo group 2 did not return and the source documentation for 5 participants was lost; for nepicastat group 3 did not return and the source documentation for 4 participants was lost).

Arm/Group Title	Placebo	Nepicastat
Arm/Group Description	Arm 1 Placebo: 100-800mg placebo	Arm 2 Nepicastat: 100-800mg
Measure Participants	44	42
Baseline	29.02 (8.03)	30.70 (7.37)
Week 2	23.66 (12.18)	24.39 (11.41)
Week 4	21.32 (12.82)	24.51 (13.06)
Week 6	20.74 (12.21)	21.32 (12.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Nepicastat
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.396
	Comments
	Method	ANOVA
	Comments
Method of Estimation	Estimation Parameter	Effect Size
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 90%; -0.35 to 0.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Effect size (ES) for change in CAPS-D score relative to baseline was calculated according to the method of Cohen.

Adverse Events

Time Frame	During six-week placebo-controlled phase.
Adverse Event Reporting Description	Adverse events were defined the same as clinicaltrials.gov. Adverse events were systematically assessed at each research visit for type of adverse event, length of time, severity, action taken, and relatedness to study medication. The source documentation was lost for 9 participants at one site (5 placebo and 4 nepicastat) and were not included in safety analysis.
Arm/Group Title	Placebo		Nepicastat
Arm/Group Description	Arm 1 Placebo: 100-800mg placebo		Arm 2 Nepicastat: 100-800mg
All Cause Mortality
	Placebo		Nepicastat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		0/45 (0%)
Serious Adverse Events
	Placebo		Nepicastat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/46 (6.5%)		2/45 (4.4%)
Cardiac disorders
Chest Pain	1/46 (2.2%)	2	1/45 (2.2%)	1
Psychiatric disorders
Psychiatric Inpatient	2/46 (4.3%)	2	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Nepicastat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/46 (54.3%)		27/45 (60%)
Ear and labyrinth disorders
Ear Pain	0/46 (0%)	0	1/45 (2.2%)	1
Eye disorders
Eye Pain	1/46 (2.2%)	1	1/45 (2.2%)	1
Dry Eye	0/46 (0%)	0	1/45 (2.2%)	1
Gastrointestinal disorders
Diarrhea	3/46 (6.5%)	3	7/45 (15.6%)	7
Gastroesophageal Reflux	2/46 (4.3%)	2	0/45 (0%)	0
Nausea	3/46 (6.5%)	3	1/45 (2.2%)	1
Vomitting	1/46 (2.2%)	1	0/45 (0%)	0
Stomach Pain	2/46 (4.3%)	2	1/45 (2.2%)	1
Dental Caries	1/46 (2.2%)	1	2/45 (4.4%)	2
Dry Mouth	3/46 (6.5%)	3	0/45 (0%)	0
General disorders
Edema Face	0/46 (0%)	0	1/45 (2.2%)	1
Fatigue	3/46 (6.5%)	3	1/45 (2.2%)	1
Infections and infestations
Gastroenteritis	2/46 (4.3%)	2	0/45 (0%)	0
Flu-like	5/46 (10.9%)	5	4/45 (8.9%)	5
sinusitis	1/46 (2.2%)	1	2/45 (4.4%)	2
MRSA staphylococcal infection	0/46 (0%)	0	1/45 (2.2%)	1
Injury, poisoning and procedural complications
injury to extremity	1/46 (2.2%)	1	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorders
muscle twitch	1/46 (2.2%)	1	0/45 (0%)	0
muscle spasm	1/46 (2.2%)	1	0/45 (0%)	0
arthralgia	2/46 (4.3%)	2	4/45 (8.9%)	4
Nervous system disorders
headache	7/46 (15.2%)	7	9/45 (20%)	9
dysgeusia (taste changes)	1/46 (2.2%)	1	0/45 (0%)	0
paraesthesia	0/46 (0%)	0	1/45 (2.2%)	1
memory problems	0/46 (0%)	0	1/45 (2.2%)	1
Psychiatric disorders
insomnia	1/46 (2.2%)	1	0/45 (0%)	0
Respiratory, thoracic and mediastinal disorders
shortness of breath	1/46 (2.2%)	1	0/45 (0%)	0
epistaxis	0/46 (0%)	0	1/45 (2.2%)	1
Skin and subcutaneous tissue disorders
rash acneiform	1/46 (2.2%)	1	2/45 (4.4%)	2
rash	1/46 (2.2%)	1	1/45 (2.2%)	1
pruritus	0/46 (0%)	0	1/45 (2.2%)	1
Surgical and medical procedures
tongue lesion removed	1/46 (2.2%)	1	0/45 (0%)	0
Vascular disorders
superficial thrombophlebitis	1/46 (2.2%)	1	0/45 (0%)	0
hypertension	0/46 (0%)	0	1/45 (2.2%)	1
hot flash	0/46 (0%)	0	1/45 (2.2%)	1

Limitations/Caveats

Limitations: short duration of placebo-controlled phase (six-weeks).

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.